Silevertinib (BDTX-1535), a covalent 4th-gen EGFR TKI, drives 60% ORR and 86% CNS responses in 1L non-classical EGFR NSCLC

Silevertinib (BDTX-1535) is a fourth-generation, covalent EGFR tyrosine kinase inhibitor designed to cover non-classical EGFR mutations (including P-loop/αC-helix–compressing [PACC] variants) with high CNS penetrance. In the Phase 2 Cohort 3 of NCT05256290 (treatment-naïve advanced NSCLC with EGFR non-classical mutations; n=43, including PACC n=25 and compound mutations n=16), ORR was 60% (26/43; 95% CI 44.4–75.0) and DCR was 91%, with CNS metastases in 37% and an intracranial ORR of 86% by RANO-BM in measurable untreated brain disease (n=6/7). Safety was EGFR-TKI–typical but dose-intense: 77% required dose reductions, 12% had serious TRAEs, and 9% discontinued for TRAEs; most common grade 3 TRAEs were rash (19%), diarrhea (19%), stomatitis (9%), and paronychia (5%)—efficacy looks directionally in-family versus afatinib benchmarks in uncommon EGFR (ORR ~60% in TKI-naïve cohorts, higher in some compound subsets), but cross-trial comparisons are messy given the unusually heterogeneous “non-classical” mix here and limited maturity on PFS/DOR (6-mo PFS 86% reported, but medians not yet shown).